The objectives of this proposal are to determine: 1) Why there is an increased fetal susceptibility to the carcinogenic effects of diethylstilbestrol, 2) What is the tumor incidence (vaginal, uterine, ovarian, renal, mammary) in this Wistar rat population following the prenatal exposure to diethylstilbestrol? 3) What additional risks are involved in exposing this diethylstilbestrol treated population to hormone therapy in the form of birth control pills and postmenopausal therapy? To answer these questions: Pharmacokinetic studies utilizing both bolus and constant infusion in vivo studies as well as individual tissue in vitro studies will be performed in the rat. These observations will be compared with in vitro early (12-20 weeks) and term human placenta studies. To date this laboratory has noted that the 14C -activity originally associated with diethylstilbestrol is more concentrated in the fetal plasma than in the maternal plasma: However, the fetal reproductive tissue concentrated the 14C to much higher levels. With the use of high pressure liquid chromatography and mass spectroscopy, the identification of the numerous oxidative metabolites and conjugates of diethylstilbestrol will be established. With this knowledge, the following question hopefully will be answered: Does the oncogenic action of diethylstilbestrol result from its estrogenic qualities or a proximate carcinogenic action? The tumor studies already in progress will be extended to establish the interactions between the pre- and postnatal hormonal therapy and their potential interactions. Thus, the distribution, metabolism and oncogenic effects of diethylstilbestrol will be intensively studied in the Wistar rat and compared with the metabolism and transport of diethylstilbestrol in the human placenta.